Interleukin-6 (IL-6) has a central role in regulating the immune response and inflammation. IL-6 has a range of biological activities, acting in an endocrine, autocrine, and paracrine fashion on a diverse number of target cells. The major sources of IL-6 are monocytes. Fibroblasts and endothelial cells along with T cells and B cells, keratinocytes, mesangial cells, and several tumor cells produce IL-6. Its synthesis is induced by IL-1, IL-2, TNF-β and interferons. IL-6 is inhibited by IL-4, IL-10, and IL-13. IL-6 thus plays an important role in immune regulation and inflammation as well as autoimmune diseases.
IL-6 has the ability to stimulate the final stages of B lymphocyte maturation, whereby B lymphocytes differentiate into mature plasma cells and secrete immunoglobulins (Ig). In addition, IL-6 induces T cell growth and cytotoxic T cell differentiation through augmentation of IL-2 receptor expression and IL-2 production. IL-6 synergizes with other cytokines to support bone marrow stem cell maturation, is a neutrophil activator and stimulates the production of platelets from megakaryocytes. It is also a potent inducer of terminal macrophage and osteoclast differentiation. IL-6 also shares several activities with IL-1 and TNF, including the induction of pyrexia and the production of acute phase proteins such as serum amyloid A, CRP, alpha 1 antitrypsin, fibrinogen, and haptoglobulin.
IL-6 mediates several unique anti-inflammatory effects. Where both IL-1 and TNF-α induce synthesis of each other, as well as IL-6, IL-6 terminates this upregulatory inflammatory cascade and inhibits IL-1 and TNF-α synthesis. IL-6 is also important as a cell growth factor that can induce proliferation of epidermal keratinocytes and mesangial cells and has an active role in mesangial proliferative glomerulonephritis.
The receptor for IL-6 (IL-6R) belongs to the type I cytokine receptor superfamily and consists of two chains, IL-6R (80 kDa glycoprotein) and gp130. IL-6R is the ligand specific binding component while gp130 is a shared receptor component responsible for transmitting intracellular signals of IL-6 related cytokines such as leukemia inhibitory factor (LIF), ciliary neurotropic factor, oncostatin M, and IL-11.
IL-6 binding to the receptor leads to dimerization of gp130, resulting in the activation of gp130 associated kinase JAK1 and subsequently tyrosine phosphorylation of gp130. Whereas gp130 is ubiquitously expressed, IL-6R is more restricted. Both IL-6R and gp130 have soluble forms. The complex of IL-6 and soluble IL-6R can act on cells expressing only gp130. This is potentially an important proinflammatory mechanism for soluble receptors.